Going down to micron scale mobile robots, the grand challenge is the limitation on scaling down onboard actuators and power sources. Two alternative approaches are proposed to solve this challenge. First, biological cells, e.g. bacteria, attached to the surface of a microrobot are used as onboard microactuators and microsensors using the chemical energy. Bacteria-propelled randomly swimming microrobots are steered using chemical and pH gradients in the environment and remote magnetic fields. As the second approach, external actuation of untethered magnetic microrobots using remote magnetic fields in enclosed spaces is demonstrated. New magnetic microrobot locomotion principles based on rotational stick-slip and rolling dynamics are proposed. Novel magnetic composite materials are used to address and control teams of microrobots. Such untethered microrobot teams are demonstrated to control microfluidic flow locally, trap live cells and transport them, and manipulate microgels with embedded cells with or without contact inside microfluidic channels for tissue engineering applications.

Most demonstrated mobile microrobot tasks so far have been achieved via pick-and-placing and dynamic trapping with teleoperation or simple path following algorithms. In our previous work, an untethered magnetic microgripper has been developed which has advanced functions, such as gripping objects. Both teleoperated manipulation in 2D and 3D have been demonstrated. However, it is challenging to control the magnetic microgripper to carry out manipulation tasks, because the grasping of objects so far in the literature relies heavily on teleoperation, which takes several minutes with even a skilled human expert. Here, we propose a new spin-walking locomotion and an automated 2D grasping motion planner for the microgripper, which enables time-efficient automatic grasping of microobjects that has not been achieved yet for untethered microrobots. In its locomotion, the microgripper repeatedly rotates about two principal axes to regulate its pose and move precisely on a surface. The motion planner could plan different motion primitives for grasping and compensate the uncertainties in the motion by learning the uncertainties and planning accordingly. We experimentally demonstrated that, using the proposed method, the microgripper could align to the target pose with error less than 0.1 body length and grip the objects within 40 seconds. Our method could significantly improve the time efficiency of micro-scale manipulation and have potential applications in microassembly and biomedical engineering.

In 2017 IEEE International Conference on Robotics and Automation (ICRA), 2017 IEEE International Conference on Robotics and Automation (ICRA), pages: 3404-3410, June 2017 (inproceedings)

Abstract

Magnetic untethered millirobots, which are actuated and controlled by remote magnetic fields, have been proposed for medical applications due to their ability to safely pass through tissues at long ranges. For example, magnetic resonance imaging (MRI) systems with a 3-7 T constant unidirectional magnetic field and 3D gradient coils have been used to actuate magnetic robots. Such magnetically constrained systems place limits on the degrees of freedom that can be actuated for untethered devices. This paper presents a design and actuation methodology for a magnetic millirobot that exhibits both position and orientation control in 2D under a magnetic field, dominated by a constant unidirectional magnetic field as found in MRI systems. Placing a spherical permanent magnet, which is free to rotate inside the millirobot and located away from the center of mass, allows the generation of net forces and torques with applied 3D magnetic field gradients. We model this system in a 3D planar case and experimentally demonstrate open-loop control of both position and orientation by the applied 2D field gradients. The actuation performance is characterized across the most important design variables, and we experimentally demonstrate that the proposed approach is feasible.

High-performance, multifunctional bacteria-driven microswimmers are introduced using an optimized design and fabrication method for targeted drug delivery applications. These microswimmers are made of mostly single Escherichia coli bacterium attached to the surface of drug-loaded polyelectrolyte multilayer (PEM) microparticles with embedded magnetic nanoparticles. The PEM drug carriers are 1 μm in diameter and are intentionally fabricated with a more viscoelastic material than the particles previously studied in the literature. The resulting stochastic microswimmers are able to swim at mean speeds of up to 22.5 μm/s. They can be guided and targeted to specific cells, because they exhibit biased and directional motion under a chemoattractant gradient and a magnetic field, respectively. Moreover, we demonstrate the microswimmers delivering doxorubicin anticancer drug molecules, encapsulated in the polyelectrolyte multilayers, to 4T1 breast cancer cells under magnetic guidance in vitro. The results reveal the feasibility of using these active multifunctional bacteria-driven microswimmers to perform targeted drug delivery with significantly enhanced drug transfer, when compared with the passive PEM microparticles.

Biohybrid cell-driven microsystems offer unparalleled possibilities for realization of soft microrobots at the micron scale. Here, we introduce a bacteria-driven microswimmer that combines the active locomotion and sensing capabilities of bacteria with the desirable encapsulation and viscoelastic properties of a soft double-micelle microemulsion for active transport and delivery of cargo (e.g., imaging agents, genes, and drugs) to living cells. Quasi-monodisperse double emulsions were synthesized with an aqueous core that encapsulated the fluorescence imaging agents, as a proof-of-concept cargo in this study, and an outer oil shell that was functionalized with streptavidin for specific and stable attachment of biotin-conjugated Escherichia coli. Motile bacteria effectively propelled the soft microswimmers across a Transwell membrane, actively delivering imaging agents (i.e., dyes) encapsulated inside of the micelles to a monolayer of cultured MCF7 breast cancer and J744A.1 macrophage cells, which enabled real-time, live-cell imaging of cell organelles, namely mitochondria, endoplasmic reticulum, and Golgi body. This in vitro model demonstrates the proof-of-concept feasibility of the proposed soft microswimmers and offers promise for potential biomedical applications in active and/or targeted transport and delivery of imaging agents, drugs, stem cells, siRNA, and therapeutic genes to live tissue in in vitro disease models (e.g., organ-on-a-chip devices) and stagnant or low-flow-velocity fluidic regions of the human body.

Biofilm colonies are typically resistant to general antibiotic treatment and require targeted methods for their removal. One of these methods includes the use of nanoparticles as carriers for antibiotic delivery, where they randomly circulate in fluid until they make contact with the infected areas. However, the required proximity of the particles to the biofilm results in only moderate efficacy. We demonstrate here that the nonpathogenic magnetotactic bacteria Magnetosopirrillum gryphiswalense (MSR-1) can be integrated with drug-loaded mesoporous silica microtubes to build controllable microswimmers (biohybrids) capable of antibiotic delivery to target an infectious biofilm. Applying external magnetic guidance capability and swimming power of the MSR-1 cells, the biohybrids are directed to and forcefully pushed into matured Escherichia coli (E. coli) biofilms. Release of the antibiotic, ciprofloxacin, is triggered by the acidic microenvironment of the biofilm, ensuring an efficient drug delivery system. The results reveal the capabilities of a nonpathogenic bacteria species to target and dismantle harmful biofilms, indicating biohybrid systems have great potential for antibiofilm applications.

Science Advances, 3(5):e1602522, American Association for the Advancement of Science, May 2017 (article)

Abstract

Dynamic self-assembled material systems constantly consume energy to maintain their spatiotemporal structures and functions. Programmable self-assembly translates information from individual parts to the collective whole. Combining dynamic and programmable self-assembly in a single platform opens up the possibilities to investigate both types of self-assembly simultaneously and to explore their synergy. This task is challenging because of the difficulty in finding suitable interactions that are both dissipative and programmable. We present a dynamic and programmable self-assembling material system consisting of spinning at the air-water interface circular magnetic micro-rafts of radius 50 μm and with cosinusoidal edge-height profiles. The cosinusoidal edge-height profiles not only create a net dissipative capillary repulsion that is sustained by continuous torque input but also enable directional assembly of micro-rafts. We uncover the layered arrangement of micro-rafts in the patterns formed by dynamic self-assembly and offer mechanistic insights through a physical model and geometric analysis. Furthermore, we demonstrate programmable self-assembly and show that a 4-fold rotational symmetry encoded in individual micro-rafts translates into 90° bending angles and square-based tiling in the assembled structures of micro-rafts. We anticipate that our dynamic and programmable material system will serve as a model system for studying nonequilibrium dynamics and statistical mechanics in the future

Bacteria biohybrids employ the motility and power of swimming bacteria to carry and maneuver microscale particles. They have the potential to perform microdrug and cargo delivery in vivo, but have been limited by poor design, reduced swimming capabilities, and impeded functionality. To address these challenge, motile Escherichia coli are captured inside electropolymerized microtubes, exhibiting the first report of a bacteria microswimmer that does not utilize a spherical particle chassis. Single bacterium becomes partially trapped within the tube and becomes a bioengine to push the microtube though biological media. Microtubes are modified with “smart” material properties for motion control, including a bacteria-attractant polydopamine inner layer, addition of magnetic components for external guidance, and a biochemical kill trigger to cease bacterium swimming on demand. Swimming dynamics of the bacteria biohybrid are quantified by comparing “length of protrusion” of bacteria from the microtubes with respect to changes in angular autocorrelation and swimmer mean squared displacement. The multifunctional microtubular swimmers present a new generation of biocompatible micromotors toward future microbiorobots and minimally invasive medical applications.

Despite the large body of experimental work recently on biohybrid microsystems, few studies have focused on theoretical modeling of such systems, which is essential to understand their underlying functioning mechanisms and hence design them optimally for a given application task. Therefore, this study focuses on developing a mathematical model to describe the 3D motion and chemotaxis of a type of widely studied biohybrid microswimmer, where spherical microbeads are driven by multiple attached bacteria. The model is developed based on the biophysical observations of the experimental system and is validated by comparing the model simulation with experimental 3D swimming trajectories and other motility characteristics, including mean squared displacement, speed, diffusivity, and turn angle. The chemotaxis modeling results of the microswimmers also agree well with the experiments, where a collective chemotactic behavior among multiple bacteria is observed. The simulation result implies that such collective chemotaxis behavior is due to a synchronized signaling pathway across the bacteria attached to the same microswimmer. Furthermore, the dependencies of the motility and chemotaxis of the microswimmers on certain system parameters, such as the chemoattractant concentration gradient, swimmer body size, and number of attached bacteria, toward an optimized design of such biohybrid system are studied. The optimized microswimmers would be used in targeted cargo, e.g., drug, imaging agent, gene, and RNA, transport and delivery inside the stagnant or low-velocity fluids of the human body as one of their potential biomedical applications.

Lab on a Chip, 17(10):1705-1724, Royal Society of Chemistry, 2017 (article)

Abstract

Untethered micron-scale mobile robots can navigate and non-invasively perform specific tasks inside unprecedented and hard-to-reach inner human body sites and inside enclosed organ-on-a-chip microfluidic devices with live cells. They are aimed to operate robustly and safely in complex physiological environments where they will have a transforming impact in bioengineering and healthcare. Research along this line has already demonstrated significant progress, increasing attention, and high promise over the past several years. The first-generation microrobots, which could deliver therapeutics and other cargo to targeted specific body sites, have just been started to be tested inside small animals toward clinical use. Here, we review frontline advances in design, fabrication, and testing of untethered mobile microrobots for bioengineering applications. We convey the most impactful and recent strategies in actuation, mobility, sensing, and other functional capabilities of mobile microrobots, and discuss their potential advantages and drawbacks to operate inside complex, enclosed and physiologically relevant environments. We lastly draw an outlook to provide directions in the veins of more sophisticated designs and applications, considering biodegradability, immunogenicity, mobility, sensing, and possible medical interventions in complex microenvironments.

The use of bacterial cells as agents of medical therapy has a long history. Research that was ignited over a century ago with the accidental infection of cancer patients has matured into a platform technology that offers the promise of opening up new potential frontiers in medical treatment. Bacterial cells exhibit unique characteristics that make them well-suited as smart drug delivery agents. Our ability to genetically manipulate the molecular machinery of these cells enables the customization of their therapeutic action as well as its precise tuning and spatio-temporal control, allowing for the design of unique, complex therapeutic functions, unmatched by current drug delivery systems. Early results have been promising, but there are still many important challenges that must be addressed. We present a review of promises and challenges of employing bioengineered bacteria in drug delivery systems and introduce the biohybrid design concept as a new additional paradigm in bacteria-based drug delivery.

Proceedings of the National Academy of Sciences, pages: 201608193, National Acad Sciences, May 2016 (article)

Abstract

Shape-programmable matter is a class of active materials whose geometry can be controlled to potentially achieve mechanical functionalities beyond those of traditional machines. Among these materials, magnetically actuated matter is particularly promising for achieving complex time-varying shapes at small scale (overall dimensions smaller than 1 cm). However, previous work can only program these materials for limited applications, as they rely solely on human intuition to approximate the required magnetization profile and actuating magnetic fields for their materials. Here, we propose a universal programming methodology that can automatically generate the required magnetization profile and actuating fields for soft matter to achieve new time-varying shapes. The universality of the proposed method can therefore inspire a vast number of miniature soft devices that are critical in robotics, smart engineering surfaces and materials, and biomedical devices. Our proposed method includes theoretical formulations, computational strategies, and fabrication procedures for programming magnetic soft matter. The presented theory and computational method are universal for programming 2D or 3D time-varying shapes, whereas the fabrication technique is generic only for creating planar beams. Based on the proposed programming method, we created a jellyfish-like robot, a spermatozoid-like undulating swimmer, and an artificial cilium that could mimic the complex beating patterns of its biological counterpart.

Lab on a Chip, 16(22):4445-4457, Royal Society of Chemistry, October 2016 (article)

Abstract

At the sub-millimeter scale, capillary forces enable robust and reversible adhesion between biological organisms and varied substrates. Current human-engineered mobile untethered micromanipulation systems rely on forces which scale poorly or utilize gripper-part designs that promote manipulation. Capillary forces, alternatively, are dependent upon the surface chemistry (which is scale independent) and contact perimeter, which conforms to the part surface. We report a mobile capillary microgripper that is able to pick and place parts of various materials and geometries, and is thus ideal for microassembly tasks that cannot be accomplished by large tethered manipulators. We achieve the programmable assembly of sub-millimeter parts in an enclosed three-dimensional aqueous environment by creating a capillary bridge between the targeted part and a synthetic, untethered, mobile body. The parts include both hydrophilic and hydrophobic components: hydrogel, kapton, human hair, and biological tissue. The 200 μm untethered system can be controlled with five-degrees-of-freedom and advances progress towards autonomous desktop manufacturing for tissue engineering, complex micromachines, microfluidic devices, and meta-materials.

Existing remotely actuated magnetic microrobots exhibit a maximum of only five-degree-of-freedom (DOF) actuation, as creation of a driving torque about the microrobot magnetization axis is not achievable. This lack of full orientation control limits the effectiveness of existing microrobots for precision tasks of object manipulation and orientation for advanced medical, biological and micromanufacturing applications. This paper presents a magnetic actuation method that allows remotely powered microrobots to achieve full six-DOF actuation by considering the case of a non-uniform magnetization profile within the microrobot body. This non-uniform magnetization allows for additional rigid-body torques to be induced from magnetic forces via a moment arm. A general analytical model presents the working principle for continuous and discrete magnetization profiles, which is applied to permanent or non-permanent (soft) magnet bodies. Several discrete-magnetization designs are also presented which possess reduced coupling between magnetic forces and induced rigid-body torques. Design guidelines are introduced which can be followed to ensure that a magnetic microrobot design is capable of six-DOF actuation. A simple permanent-magnet prototype is fabricated and used to quantitatively demonstrate the accuracy of the analytical model in a constrained-DOF environment and qualitatively for free motion in a viscous liquid three-dimensional environment. Results show that desired forces and torques can be created with high precision and limited parasitic actuation, allowing for full six-DOF actuation using limited feedback control

2015

In 2015 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS), 2015 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS), pages: 1706-1711, September 2015 (inproceedings)

Abstract

This paper presents a new soft-bodied millimeterscale swimmer actuated by rotating uniform magnetic fields. The proposed swimmer moves through internal undulatory deformations, resulting from a magnetization profile programmed into its body. To understand the motion of the swimmer, a mathematical model is developed to describe the general relationship between the deflection of a flexible strip and its magnetization profile. As a special case, the situation of the swimmer on the water surface is analyzed and predictions made by the model are experimentally verified. Experimental results show the controllability of the proposed swimmer under a computer vision-based closed-loop controller. The swimmers have nominal dimensions of 1.5×4.9×0.06 mm and a top speed of 50 mm/s (10 body lengths per second). Waypoint following and multiagent control are demonstrated for swimmers constrained at the air-water interface and underwater swimming is also shown, suggesting the promising potential of this type of swimmer in biomedical and microfluidic applications.

This chapter discusses the methods and state of the art in microscale manipulation in remote environments using untethered microrobotic devices. It focuses on manipulation at the size scale of tens to hundreds of microns, where small size leads to a dominance of microscale physical effects and challenges in fabrication and actuation. To motivate the challenges of operating at this size scale, the chapter includes coverage of the physical forces relevant to microrobot motion and manipulation below the millimeter-size scale. It then introduces the actuation methods commonly used in untethered manipulation schemes, with particular focus on magnetic actuation due to its wide use in the field. The chapter divides these manipulation techniques into two types: contact manipulation, which relies on direct pushing or grasping of objects for motion, and noncontact manipulation, which relies indirectly on induced fluid flow from the microrobot motion to move objects without any direct contact.

Untethered robots miniaturized to the length scale of millimeter and below attract growing attention for the prospect of transforming many aspects of health care and bioengineering. As the robot size goes down to the order of a single cell, previously inaccessible body sites would become available for high-resolution in situ and in vivo manipulations. This unprecedented direct access would enable an extensive range of minimally invasive medical operations. Here, we provide a comprehensive review of the current advances in biomedical untethered mobile milli/microrobots. We put a special emphasis on the potential impacts of biomedical microrobots in the near future. Finally, we discuss the existing challenges and emerging concepts associated with designing such a miniaturized robot for operation inside a biological environment for biomedical applications.

Lab on a Chip, 15(7):1667-1676, Royal Society of Chemistry, January 2015 (article)

Abstract

Three-dimensional (3D) heterogeneous assembly of coded microgels in enclosed aquatic environments is demonstrated using a remotely actuated and controlled magnetic microgripper by a customized electromagnetic coil system. The microgripper uses different ‘stick–slip’ and ‘rolling’ locomotion in 2D and also levitation in 3D by magnetic gradient-based pulling force. This enables the microrobot to precisely manipulate each microgel by controlling its position and orientation in all x–y–z directions. Our microrobotic assembly method broke the barrier of limitation on the number of assembled microgel layers, because it enabled precise 3D levitation of the microgripper. We used the gripper to assemble microgels that had been coded with different colours and shapes onto prefabricated polymeric microposts. This eliminates the need for extra secondary cross-linking to fix the final construct. We demonstrated assembly of microgels on a single micropost up to ten layers. By increasing the number and changing the distribution of the posts, complex heterogeneous microsystems were possible to construct in 3D.

2014

As we move towards the miniaturization of devices to perform tasks at the nano and microscale, it has become increasingly important to develop new methods for actuation, sensing, and control. Over the past decade, bio-hybrid methods have been investigated as a promising new approach to overcome the challenges of scaling down robotic and other functional devices. These methods integrate biological cells with artificial components and therefore, can take advantage of the intrinsic actuation and sensing functionalities of biological cells. Here, the recent advancements in bio-hybrid actuation are reviewed, and the challenges associated with the design, fabrication, and control of bio-hybrid microsystems are discussed. As a case study, focus is put on the development of bacteria-driven microswimmers, which has been investigated as a targeted drug delivery carrier. Finally, a future outlook for the development of these systems is provided. The continued integration of biological and artificial components is envisioned to enable the performance of tasks at a smaller and smaller scale in the future, leading to the parallel and distributed operation of functional systems at the microscale.

We have developed a millimeter-scale magnetically driven swimming robot for untethered motion at mid to low Reynolds numbers. The robot is propelled by continuous undulatory deformation, which is enabled by the distributed magnetization profile of a flexible sheet. We demonstrate control of a prototype device and measure deformation and speed as a function of magnetic field strength and frequency. Experimental results are compared with simple magnetoelastic and fluid propulsion models. The presented mechanism provides an efficient remote actuation method at the millimeter scale that may be suitable for further scaling down in size for microrobotics applications in biotechnology and healthcare

Our goal is to understand the principles of Perception, Action and Learning in autonomous systems that successfully interact with complex environments and to use this understanding to design future systems